History of Erythropoiesis-Stimulating Agents, the Development of Biosimilars, and the Future of Anemia Treatment in Nephrology.

BACKGROUND: Exogenous replacement of erythropoietin (EPO) by recombinant human EPO has been considered a standard of care for the treatment of anemia in patients with chronic kidney disease for more than 20 years. Genetically engineered biologic proteins derived from human, animal, or microorganism sources are a major area of growth in modern medical care, accounting for one-third of new drug approvals in the past decade. Despite benefit to patients, the use of biologics comes at a significant cost, representing one of the fastest growing segments of strained healthcare budgets around the world. SUMMARY: Biosimilars, or biologic drugs that are designed to be highly similar to approved reference biologic drugs, have been available in Europe for more than 10 years with no unusual or unexpected effects compared to their reference biologics whose patents have expired. Given the success of the biosimilar approval pathway pioneered in Europe, it has served as a global reference for other regulatory authorities to establish and implement biosimilar licensure frameworks, including the United States (US), the largest pharmaceutical market in the world. Given 10 of the top 25 drugs sold in 2014 were biologics, and considering the rising costs of healthcare, biosimilars have the potential to become a significant part of the US market. Key Messages: For the nephrology community, the recent patent expiries for epoetin alfa (Epogen®, Amgen and Procrit®, Johnson & Johnson) have created the opportunity to develop biosimilar EPOs. And while no biosimilar in this therapeutic class is approved in the US, there are proposed biosimilars in development.

2009: a requiem for rHuEPOs--but should we nail down the coffin in 2010?

The recombinant human erythropoietins and allied proteins (epoetin alfa, attempted copies and biosimilar variants of epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine. This article charts a brief history of their use in clinical medicine, mainly dealing with chronic kidney disease, paying special attention to how these agents were introduced into clinical medicine and what has happened subsequently; in 2009, there were several developments that could be regarded as a "perfect storm" in terms of the long-term use of these compounds in chronic kidney disease and oncology and, likely, elsewhere. We are now very much at a "crossroads," where mature reflection is required, because with the latest trials and meta-analyses, these therapies seem not only expensive but also very much a clinical tradeoff (increased risk of adverse effects versus a small gain in fatigue scores). How we arrived at this crossroads is a useful illustration of how easy it is, without properly designed randomized, controlled trials, to assume that clinical benefit must follow therapeutic interventions.

Evolution of iv iron compounds over the last century.

Administration of intravenous (IV) iron has become pivotal in the management of anaemia in patients with chronic kidney disease (CKD). Since parenteral iron was first introduced for human use in the 1930s, things have come a long way. Seventy years ago, iron was toxic, administered as an iron oxyhydroxide complex. This problem was circumvented with the introduction of compounds containing iron in a core surrounded by a carbohydrate shell. The carbohydrate shell consists of molecules such as dextran, sucrose, dextrin or gluconate. The first dextran-containing IV iron preparations carried a small risk of anaphylaxis, but the more recently introduced low molecular weight iron dextran preparation has significantly less risk of this. Iron reactions occur with all IV iron preparations, but are generally not thought to be immune based. Recently, newer IV iron preparations have appeared in the market, including Ferumoxytol (Feraheme) and ferric carboxymaltose (Ferinject). These latest IV iron preparations do not contain a requirement for a test dose, and a much higher dose of iron can be delivered as a single administration. Thus, giving supplemental iron to man has come a long way since 1930s; we are now in an era when we are able to administer higher doses of iron with acceptable safety and without significant adverse effects. However, the long-term safety of the newer IV iron preparations is not yet established.

A brief history in nephrology pharmacotherapy.

Advances in drug therapy for patients with kidney disease have contributed to increased exercise capacity, reduced cardiovascular disease, decreased renal bone disease, improved quality of life, and most importantly, reduced morbidity and mortality. New insights into the pathophysiology of chronic kidney disease (CKD) have helped lead to the development of many novel drugs and treatments. The purpose of this article is to highlight some of the developments in nephrology pharmacotherapy that occurred during the first 40 years of the American Nephrology Nurses' Association.